Esketamine as an Adjuvant to Ropivacaine in Genicular Nerve and IPACK Blocks for Total Knee Arthroplasty: A Double-Blind Randomized Trial

Abstract

Purpose: Chronic postsurgical pain (CPSP) following total knee arthroplasty (TKA) affects up to 44% of patients and markedly impairs recovery and quality of life. Although regional anesthesia is integral to multimodal analgesia, its preventive effect on CPSP remains limited. Esketamine, a potent N-methyl-D-aspartate receptor antagonist with analgesic and neuroprotective properties, may enhance local anesthetic efficacy and reduce the development of chronic pain. Patients and Methods: In this prospective, randomized, double-blind trial, 367 patients undergoing unilateral TKA under general anesthesia with peripheral nerve blocks were allocated to three groups: CTRL (normal saline), ROP (0.5% ropivacaine), and ESK (0.5% ropivacaine plus esketamine 0.2 mg/kg) for genicular nerve and IPACK blocks. The primary outcome was the incidence of CPSP (Numerical Rating Scale ≥ 4) at 6 months. Secondary outcomes included opioid consumption, NRS pain scores, Timed Up and Go (TUG) test, walking distance, Quality of Recovery-15 (QoR-15) scores, and adverse events. Results: At 6 months, the incidence of CPSP was significantly lower in the ESK group (4.9%) than in the ROP (17.9%) and CTRL (27.0%) groups. Esketamine significantly reduced overall pain burden (AUC = 559.3 ± 59.0 vs 641.9 ± 55.8 and 679.2 ± 58.5; P < 0.0001). It also lowered 24-hour opioid consumption, with patients in the ESK group requiring less morphine equivalent (26.8 ± 11.5 mg) compared with the ROP (29.7 ± 11.8 mg) and CTRL (34.8 ± 11.9 mg) groups (P < 0.001). Functional recovery improved, with shorter TUG times, longer walking distance, and higher QoR-15 scores. No serious adverse events or psychomimetic reactions were reported. Conclusion: Esketamine as an adjuvant to ropivacaine in genicular and IPACK blocks significantly reduced CPSP incidence and improved early functional recovery after TKA without increasing adverse effects. Perineural esketamine may represent a safe and effective strategy to prevent pain chronification.